Head and neck squamous cell carcinomas (HNSCC) are the eighth most common cause of cancer death worldwide.1 In Southeast Asia and Africa, head and neck cancers account for approximately 8% to 10% of all cancers.2
An early stage HNSCC can be curable with surgery or radiotherapy treatment alone, with a 5-year overall survival rate of 80% to 90% for a Stage I disease and 65% to 80% for a Stage II.3–6 However, approximately 60% of patients are diagnosed with advanced diseases (stages III or IV).7 The advanced HNSCC without distant metastasis is still a potentially curable disease, but the prognosis is poorer than the early stage diseases. Treating advanced HNSCC is still a challenge for head and neck surgeons. With a combined-modality therapy, the 5-year overall survival rate reaches 30% to 50% for unresectable tumors and approximately 40% for resectable tumors.8–12
For HNSCC patients, chemotherapy by itself is not a curative treatment modality, but it may be used as a neoadjuvant (induction) chemotherapy, a concomitant (concurrent) chemoradiotherapy or an adjuvant chemotherapy.13 The administration of the neoadjuvant chemotherapy in HNSCC patients has several potential benefits. First, combined with neoadjuvant chemotherapy, locoregional treatment demonstrates a higher organ preservation rate.14,15 Second, neoadjuvant chemotherapy can facilitate a surgical resection by downstaging tumors. Theoretically, chemotherapy can increase the overall survival rate by providing a better locoregional control and an early treatment of micrometastatic disease. However, chemotherapy failed to show any survival benefit in several randomized control trials in the neoadjuvant chemotherapy groups.16–29 Only one trial demonstrated a small but significant benefit in the overall survival rate of the neoadjuvant chemotherapy group.30
The PF regimen (cisplatin and fluorouracil) was once regarded as the most effective and standard neoadjuvant chemotherapy regimen for treating HNSCC before the emergence of Taxanes. However its benefit for improving the survival rate still remains controversial. The aim of this meta-analysis was to evaluate the role of this regimen in enhancing the overall survival of and decreasing locoregional relapse and distant metastasis in HNSCC patients.
Data collection and selection
Medline and manual searches were carried out to identify all published RCTs that compared the neoadjuvant chemotherapy with the PF regimen plus locoregional treatment to only locoregional treatment for advanced HNSCC. The search was done on PudMed using three sets of terms: “head neck/oral/oropharyngeal/hypopharyngeal/maxillofacial/laryngeal/paranasal sinus”, “carcinoma” and “neoadjuvant/induction/preoperative chemotherapy”. A limit was set on the Randomized Controlled Trials and the terms were set to title/abstract. Twenty-one searches were performed with a combination of 3 terms for each set. In total, 80 articles were found, and the references of these articles and the related articles were reviewed to identify all the RCTs.
The data of the RCTs were eligible if they fit the following criteria. (1) The data of the randomized control trials were officially published, and they were clearly demonstrated in the articles. (2) Patients were eligible if they were suffering from a previously untreated stage III or IV head and neck squamous cell carcinoma without metastasis. Some trials including patients with a stage II tumor was not excluded. Primary sites included the oral cavity, the larynx, the pharynx and the maxillary sinus. Nasopharyngeal carcinomas were excluded because of their unique characteristics in epidemiology, histologic features (histology), and treatment modality.31 (3) Treatment modality was confined to a neoadjuvant chemotherapy followed by a locoregional treatment for the treatment group and a locoregional treatment alone for the control group. Locoregional treatment included surgery, radiotherapy, or the combination of both. Concomitant or concurrent radiochemotherapies were excluded. In the same trial, the locoregional treatment of the treatment group and the control group must be performed equally. (4) The regimen of the neoadjuvant chemotherapy was confined to a PF regimen (3 or 4 cycles).
The data of each RCT were collected by Dr. SU Yu-xiong and Dr. ZHENG Guang-sen independently. The results were consistent.
Data were obtained directly from included articles or calculated by percentage in each article. The meta-analysis was performed using a Review Manager 22.214.171.124 software (provided by Cochrane Collaboration). Outcomes assessed by this meta-analysis included the overall survival, locoregional relapse, and distant metastasis. Overall survival was defined as the time between the treatment randomization and the date of the last follow-up or of the patient's death. Patients who failed to follow-up were considered as dead. Locoregional recurrence and distant metastasis were measured from the date of treatment randomization to the occurrence of either event or to the date of last follow-up. Heterogeneity between the trials was assessed to determine which model would be used in the meta-analysis. A sensitivity analysis was performed by changing the meta-analysis model. An odds ratio was the principle measurement of effect. It was calculated as the treatment group (chemotherapy and locoregional treatment) versus the control group (locoregional treatment alone).
All statistical analyses were performed spontaneously using Review Manager 126.96.36.199 software. Heterogeneity between the trials was assessed using chi-square test. The odds ratios (ORs) were presented with a 95% confidence interval (CI). P values of <0.05 were considered statistically significant.
Eight RCTs were identified, and the quality scores of the RCTs were assessed according to the method of Jadad.32 The details are shown in Table. In RCT No. 1 (by Paccagnella et al30), the patients underwent 4 cycles of PF chemotherapy. In other studies, the patients received 3 cycles of PF chemotherapy. A study by Tejedor et al17 using carboplatin instead of cisplatin in the PF regime was also included in our analysis. The RCT quality scores ranged from 1 to 3 (5-point scale), with a mean of 2.3.
Meta-analysis of locoregional relapse
There was no significant heterogeneity between the trials (P=0.91), and the fixed effects meta-analysis model (Peto's method) was used.
In the 8 RCTs, the data in studies 1, 2, 3, 6, 8 were available for the analysis of locoregional relapse. In these 5 studies, the difference of the locoregional relapse between the treatment group and the control group was not statistically significant.
There were 510 patients in the treatment group and 509 patients in the control group in this meta-analysis. The odds ratio (95% CI; P value), expressed as the treatment group versus the control group, was 0.92 (0.70, 1.22; P=0.57). The difference of the locoregional relapse between the treatment group and the control group was not statistically significant (Figure 1).
All studies or sub-categories are shown in Table. Each trial is represented by a square, the center of which gives the odds ratio for that trial. The size of square is proportional to the information in that trial. The ends of the horizontal bars denote a 95% CI. The black diamond gives the overall odds ratio for the combined results of all trials. The center of it denotes the odds ratio, and the extremities denote the 95% CI. The symbols mentioned above are the same as ones used in Figures 2–6.
A sensitivity analysis was performed by changing the effect model into the random effect model. The results showed that the difference of the locoregional relapse between the treatment group and the control group was not statistically significant, neither. The results of the fixed effect model and the random effect model coordinated with each other (Figure 2).
Meta-analysis of distant metastasis
There was no significant heterogeneity between the trials (P=0.28), and the fixed effects meta-analysis model (Peto's method) was used.
In the 8 RCTs, the data in studies 1, 2, 3, 6, 8 were available for the analysis of distant metastasis. In studies 2, 3, 6, 8, the difference of distant metastasis between the treatment group and the control group was not statistically significant. The difference of distant metastasis between the treatment group and the control group in study 1 was statistically significant.
There were 510 patients in the treatment group and 509 patients in the control group in this meta-analysis. The odds ratio (95% CI; P value), expressed as the treatment group versus the control group, was 0.47 (0.33, 0.68; P <0.05). The difference of distant metastasis between the treatment group and the control group was statistically significant. The distant metastasis was reduced by 52% in the treatment group compared to the control group (Figure 3).
A sensitivity analysis was performed by changing the effect model into the random effect model. The results showed that the difference of distant metastasis between the treatment group and the control group was statistically significant when the random effect model was used. The results of the fixed effect model and the random effect model coordinated with each other (Figure 4).
Meta-analysis of overall survival
There was no significant heterogeneity between the trials (P=0.21), and the fixed effects meta-analysis model (Peto's method) was used.
In the 8 RCTs, the data in studies 1, 2, 3, 4, 5, 6, 7, 8 were available for the analysis of overall survival. The difference of overall survival between the treatment group and the control group in each study was not statistically significant.
There were 626 patients in the treatment group and 633 patients in the control group in this meta-analysis. The odds ratio (95% CI; P value), expressed as treatment group versus control group, was 1.28 (1.01, 1.62; P=0.04). The difference of the overall survival between the treatment group and the control group was statistically significant. The overall survival was increased by 28% in the treatment group compared to the control group (Figure 5).
A sensitivity analysis was performed by changing the effect model into the random effect model. The results showed that the confidence interval of the odds ratio lay across the non-effect line, and the difference of the overall survival between the treatment group and the control group was not statistically significant when the random effect model was used. The results of the fixed effect model and the random effect model contradicted with each other, suggesting that the results were not sensitive (Figure 6).
The treatment of the HNSCC is dependent on the TMN staging of the tumor. The advanced stage (stage III-IVB) HNSCCs without the evidence of distant metastasis are still potentially curable, but the prognosis is relatively poor compared to an early stage disease. These patients require a combination of modality therapy, including surgery, chemotherapy and radiotherapy. Surgery is the best treatment for operable tumors, and radiotherapy for inoperable tumors. Chemotherapy is an adjuvant treatment modality in the form of adjuvant chemotherapy, neoadjuvant chemotherapy and concomitant chemoradiotherapy.13 Yet, the administration of the neoadjuvant chemotherapy is still controversial. Neoadjuvant chemotherapy has its advantages. First, patients tolerate neoadjuvant chemotherapy well. Second, neoadjuvant chemotherapy provides a better control of micrometastasis.33 Third, neoadjuvant chemotherapy might downstage the tumor and facilitates the surgery.34 However, it might delay the curative treatment if the tumor does not respond to the neoadjuvant chemotherapy, which is also costly. Theoretically, neoadjuvant chemotherapy might increase the survival rate and improve the quality of life. However, most randomized control trials failed to show any benefit in the overall survival of the neoadjuvant groups over the control groups. This might be attributed to the sample size of each trial, which could be too underpowered to demonstrate any positive results. The meta-analysis of Pignon et al35 failed to show an effect of the neoadjuvant chemotherapy on survival when the regimen was not confined to a PF regimen. However, it showed a small but significant benefit in survival when the neoadjuvant chemotherapy group was confined to PF regimen. The result coincided with this study, which shows that neoadjuvant chemotherapy with a PF regimen has a small benefit on the overall survival of HNSCC patients.
Mortality directly links with treatment failure, which mainly comprises of locoregional relapse, secondary primary malignancy, and distant metastasis. In this meta-analysis, the outcomes of locoregional relapse and distant metastasis were analyzed. The difference of locoregional relapse was not statistically significant between the neoadjuvant chemotherapy group and the control group, which suggests that neoadjuvant chemotherapy with a PF regimen has no effect on the locoregional control of HNSCC when a locoregional treatment is performed. Distant metastasis was reduced significantly in the neoadjuvant chemotherapy group than in the control group. The result supports that there are micrometastasis foci preexisting in the M0 disease, and neoadjuvant chemotherapy with a PF regimen provides a better control of the micrometastasis foci. In the neoadjuvant chemotherapy group, distant metastatic rate was relatively low which leads to a minor improvement on overall survival. This is the first meta-analysis showing that neoadjuvant chemotherapy with a PF regimen improves overall survival mainly by providing a better control of the micrometasis foci rather than the control of the locoregional relapse.
The regimen of the neoadjuvant chemotherapy might affect the outcome of the treatment. Several regimens have been used in the neoadjuvant chemotherapy of HNSCC, and the PF regimen has been once regarded as the most effective one before the emergence of taxanes. The incorporation of taxanes into the PF regimen makes up the TPF regimen, which is a promising regimen of the treatment HNSCC. However, its effectiveness is yet to be confirmed.
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